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HAND transcription factors cooperatively specify the aorta and pulmonary trunk
Congenital heart defects (CHDs) affecting the cardiac outflow tract (OFT) constitute a significant cause of morbidity and mortality. The OFT develops from migratory cell populations which include the cardiac neural crest cells (cNCCs) and secondary heart field (SHF) derived myocardium and endocardium. The related transcription factors HAND1 and HAND2 have been implicated in human CHDs involving the OFT. Although Hand1 is expressed within the OFT, Hand1 NCC-specific conditional knockout mice (H1CKOs) are viable. Here we show that these H1CKOs present a low penetrance of OFT phenotypes, whereas SHF-specific Hand1 ablation does not reveal any cardiac phenotypes. Further, HAND1 and HAND2 appear functionally redundant within the cNCCs, as a reduction/ablation of Hand2 on an NCC-specific H1CKO background causes pronounced OFT defects. Double conditional Hand1 and Hand2 NCC knockouts exhibit persistent truncus arteriosus (PTA) with 100% penetrance. NCC lineage-tracing and Sema3c in situ mRNA expression reveal that Sema3c-expressing cells are mis-localized, resulting in a malformed septal bridge within the OFTs of H1CKO;H2CKO embryos. Interestingly, Hand1 and Hand2 also genetically interact within the SHF, as SHF H1CKOs on a heterozygous Hand2 background exhibit Ventricular Septal Defects (VSDs) with incomplete penetrance. Previously, we identified a BMP, HAND2, and GATA-dependent Hand1 OFT enhancer sufficient to drive reporter gene expression within the nascent OFT and aorta. Using these transcription inputs as a probe, we identify a novel Hand2 OFT enhancer, suggesting that a conserved BMP-GATA dependent mechanism transcriptionally regulates both HAND factors. These findings support the hypothesis that HAND factors interpret BMP signaling within the cNCCs to cooperatively coordinate OFT morphogenesis.
Noonan syndrome patient-specific induced cardiomyocyte model carrying SOS1 gene variant c.1654A>G
Noonan syndrome (NS) is a dominant autosomal genetic disorder, associated with mutations in several genes that exhibit multisystem abnormal development including cardiac defects. NS associated with the Son of Sevenless homolog 1 (SOS1) gene mutation attributes to the development of cardiomyopathy and congenital heart defects. Since the treatment option for NS is very limited, an in vitro disease model with SOS1 gene mutation would be beneficial for exploring therapeutic possibilities for NS. We reprogrammed cardiac fibroblasts obtained from a NS patient and normal control skin fibroblasts (C-SF) into induced pluripotent stem cells (iPSCs). We identified NS-iPSCs carry a heterozygous single nucleotide variation in the SOS1 gene at the c.1654A > G. Furthermore, the control and NS-iPSCs were differentiated into induced cardiomyocytes (iCMCs), and the electron microscopic analysis showed that the sarcomeres of the NS-iCMCs were highly disorganized. FACS analysis showed that 47.5% of the NS-iCMCs co-expressed GATA4 and cardiac troponin T proteins, and the mRNA expression levels of many cardiac related genes, studied by qRT-PCR array, were significantly reduced when compared to the control C-iCMCs. We report for the first time that NS-iPSCs carry a single nucleotide variation in the SOS1 gene at the c.1654A>G were showing significantly reduced cardiac genes and proteins expression as well as structurally and functionally compromised when compared to C-iCMCs. These iPSCs and iCMCs can be used as a modeling platform to unravel the pathologic mechanisms and also the development of novel drug for the cardiomyopathy in patients with NS.
Genomic analyses implicate noncoding de novo variants in congenital heart disease
A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n = 2,238 DNVs) compared to controls (n = 4,177; P = 8.7 × 10 -4 ). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10 -5 ). We observed significant overlap between these transcription-based approaches (odds ratio (OR) = 2.5, 95% confidence interval (CI) 1.1-5.0, P = 5.4 × 10 -3 ). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. Finally, we observed a DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1-1.2, P = 8.8 × 10 -5 ). Overall, our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as that observed for damaging coding DNVs.
Implication of rare genetic variants of NODAL and ACVR1B in congenital heart disease patients from Indian population
Highlights: • Screening of 300 CHD patients revealed two rare missense variants (p.P51L & p.D327E) in NODAL. • A novel missense variation p.M345I was identified in ACVR1B. • Bioinformatic analyses suggested that these variants could have deleterious role. • Three-dimensional modelling suggested conformation changes in the mutated proteins compared to wild-type. • In vitro studies demonstrated that missense variants affect the function of NODAL and ACVR1B. NODAL signaling plays an essential role in vertebrate embryonic patterning and heart development. Accumulating evidences suggest that genetic mutations in TGF-β/NODAL signaling pathway can cause congenital heart disease in humans. To investigate the implication of NODAL signaling in isolated cardiovascular malformation, we have screened 300 non-syndromic CHD cases and 200 controls for NODAL and ACVR1B by Sanger sequencing and identified two rare missense (c.152C > T; p.P51L and c.981 T > A; p.D327E) variants in NODAL and a novel missense variant c.1035G > A; p.M345I in ACVR1B. All these variants are absent in 200 controls. Three-dimensional protein-modelling demonstrates that both p.P51L and p.D327E variations of NODAL and p.M345I mutation of ACVR1B, affect the tertiary structure of respective proteins. Variants of NODAL (p.P51L and p.D327E) and ACVR1B (p.M345I), significantly reduce the transactivation of AR3-Luc, (CAGA){sub 12}-Luc and (SBE){sub 4}-Luc promoters. Moreover, qRT-PCR results have also deciphered a reduction in the expression of cardiac-enriched transcription factors namely Gata4, Nkx2-5, and Tbx5 in both the mutants of NODAL. Decreased expression of, Gata4, Nkx2-5, Tbx5, and lefty is observed in p.M345I mutant of ACVR1B as well. Additionally, reduced phosphorylation of SMAD2/3 in response to these variants, suggests impaired NODAL signaling and possibly responsible for defective cell fate decision and differentiation of cardiomyocytes leading to CHD phenotype.
Identification of ancestral gnathostome Gli3 enhancers with activity in mammals
Abnormal expression of the transcriptional regulator and hedgehog (Hh) signaling pathway effector Gli3 is known to trigger congenital disease, most frequently affecting the central nervous system (CNS) and the limbs. Accurate delineation of the genomic cis-regulatory landscape controlling Gli3 transcription during embryonic development is critical for the interpretation of noncoding variants associated with congenital defects. Here, we employed a comparative genomic analysis on fish species with a slow rate of molecular evolution to identify seven previously unknown conserved noncoding elements (CNEs) in Gli3 intronic intervals (CNE15–21). Transgenic assays in zebrafish revealed that most of these elements drive activities in Gli3 expressing tissues, predominantly the fins, CNS, and the heart. Intersection of these CNEs with human disease associated SNPs identified CNE15 as a putative mammalian craniofacial enhancer, with conserved activity in vertebrates and potentially affected by mutation associated with human craniofacial morphology. Finally, comparative functional dissection of an appendage-specific CNE conserved in slowly evolving fish (elephant shark), but not in teleost (CNE14/hs1586) indicates co-option of limb specificity from other tissues prior to the divergence of amniotes and lobe-finned fish. In conclusion, these results uncover a novel subset of intronic Gli3 enhancers that arose in the common ancestor of gnathostomes and whose sequence components were likely gradually modified in other species during the process of evolutionary diversification.